IL-8 receptor antagonists

Abstract

This invention relates to novel phenyl ureas useful in the treatment of disease states mediated by the chemokine, Interleukin-3 (IL-3)

What is claimed is:  
     
         1 . A method of treating a chemokine mediated disease state, selected from the group consisting of malaria, restinosis, anoiogenesis atherosclerosis, osteoporosis, gingivitis, undesired hematopoietic stem cells release and diseases caused by respiratory viruses herpesviruses, and hepatitis viruses, wherein the chemokine binds to an IL-8 α or β receptor in a mammal, which comprises administerinn to said mammal an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 X is oxygen or sulfur;  
 R is (CR 8 R 8 )r C(O) 2 H, (CR 8 R 8 )r NH—C(O)R a , (CR 8 R 8 )r C(O)NR 6′ R 7′ , (CR 8 R 8 )r NHS(O) 2 R b , (CR 8 R 8 )r S(O) 2 NHR c , (CR 8 R 8 )r NHC(X 2 )NHR b , or a tetrazolyl ring;  
 X 2  is oxygen or sulfur;  
 R 1  is independently selected from hydrogen; halogen: nitro; cyano; halosubstituted C 1-10  alkyl; C 1-10  alkyl; C 2-10  alkenyl; C 1-10  alkoxy; halosubstituted C 1-10  alkoxy; (CR 8 R 8 )q S(O) t R 4 ; hydroxy; hydroxy C 1-4 alkyl; aryl; aryl C 1-4  alkyl; aryloxy; aryl C 1-4  alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic C 1-4 alkyl: heteroaryl C 1-4  alkyloxy; aryl C 2-10  alkenyl; heteroaryl C 2-10  alkenyl; heterocyclic C 2-10  alkenyl; (CR 8 R 8 )qNR 4 R 5 ; C 2-10  alkenyl C(O)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 10 ; S(O) 3 R 8 ; (CR 8 R 8 )q C(O)R 11 ; C) 2-10 alkenyl C(O)R 11 ; C 2-10 alkenyl C(O)OR 11 (CR 8 R 8 )q C(O)OR 12 ; (CR 8 R 8 )q OC(O) R 11 ; (CR 8 R 8 )qNR 4 C(O)R 11 (CR 8 R 8 )q NHS(O) 2 R 17 ; (CR 8 R 8 )q S(O) 2 NR 4 R 5 ; or two R 1  moieties together may form O—(CH 2 ) s O— or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may be optionally substituted;  
 n is an integer having a value of 1 to 3;  
 m is an integer having a value of 1 to 3;  
 q is 0, or an integer having a value of 1 to 10;  
 r is 0, or an integer having a value of 1 to 4;  
 s is an integer having a value of 1 to 3;  
 t is 0, or an integer having a value of 1 or 2;  
 v is an integer having a value of 1 to 4;  
 R 4  and R 5  are independently hydrogen, optionally substituted C 1-4  alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1-4 alkyl, heterocyclic, or heterocyclic C 1-4  alkyl. or R 4  and R 5  together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;  
 R 6  and R 7  are independently hydrogen or a C 1-4  alkyl group, or R 6  and R 7  together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;  
 R 6′ , and R 7′  are independently hydrogen, C 1-4  alkyl, aryl, arylC 1-4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroarylC 1-4 alkyl, heteroarylC 2-4  alkenyl, heterocyclic, heterocyclic C 1-4 alkyl, heterocyclic C 2-4 alkenyl moiety, provided that one of R 6′  and R 7′  are hydrogen. but not both;  
 Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C 1-10  alkyl; C 1-10  alkyl; C 2-10  alkenyl; C 1-10  alkoxy; halosubstituted C 1-10  alkoxy; azide; (CR 8 R 8 )q S(O) t R 4 ; hydroxy: hydroxyC 1-4 alkyl; aryl; aryl C 1-4  alkyl; aryloxy; arylC 1-4  alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C 1-4  alkyloxy; heterocyclic, heterocyclic C 1-4 alkyl; aryl C 1-10  alkenyl; heteroaryl C 2-10  alkenyl; heterocyclic C 2-10  alkenyl; (CR 8 R 8 )q NR 4 R 5 ; C 2-10  alkenyl C(O)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 10 ; S(O) 3 H; S(O) 3 R 8 ; (CR 8 R 8 )q C(O)R 11 ; C 2-10  alkenyl C(O)R 11 ; C 2-10  alkenyl C(O)OR 11 ; C(O)R 11 ; (CR 8 R 8 )q C(O)OR 12 ; (CR 8 R 8 )q OC(O) R 11 ; (CR 8 R 8 )qNR 4 C(O)R 11 ; (CR 8 R 8 )q NHS(O) 2 R d ; (CR 8 R 8 )q S(O) 2 NR 4 R 5 ; or two Y moieties together may form O—(CH 2 ) s O— or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may be optionally substituted;  
 R 8  is independently selected from hydrogen or C 1-4  alkyl;  
 R 10  is C 1-10  alkyl C(O) 2 R 8 ;  
 R 11  is hydrogen, C 1-4  alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1-4 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1-4 alkyl;  
 R 12  is hydrogen, C 1-10  alkyl, optionally substituted aryl or optionally substituted arylalkyl;  
 R 13  and R 14  are independently hydrogen, optionally substituted C 1-4  alkyl, or one of R 13  and R 14  may be optionally substituted aryl;  
 R 17  is C 1-4 alkyl, aryl, arylalkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclic, or heterocyclicC 1-4 alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;  
 R a  is an alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic, or a heterocyclic C 1-4 alkyl moiety, wherein all of these moieties may be optionally substituted;  
 R b  is a NR 6 R 7 , alkyl, aryl, arylC 1-4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroarylC 1-4 alkyl, heteroarylC 2-4  alkenyl, heterocyclic, heterocyclic C 1-4 alkyl, heterocyclic C 2-4 alkenyl moiety, or camphor, wherein all of these moieties may be optionally substituted.  
 R c  is alkyl, aryl, arylC 1-4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroarylC 1-4 alkyl, heteroarylC 2-4 alkenyl, heterocyclic, heterocyclic C 1-4 alkyl, or a heterocyclic C 2-4 alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted C 1-4  alkyl, C 1-4  alkyl, C 1-4  alkoxy, NR 9 C(O)R a , C(O)NR 6 R 7 , S(O) 3 H, or C(O)OC 1-4  alkyl;  
 R d  is NR 6 R 7 , alkyl, arylC 1-4  alkyl, arylC 2-4  alkenyl, heteroaryl, heteroaryl-C 1-4 alkyl, heteroarylC 2-4  alkenyl, heterocyclic, or heterocyclicC 1-4  alkyl, wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted;  
                     
 the E containing ring is optionally selected from  
                     
 the asterix * denoting point of attachment of the ring;  
 R 20  is W 1 , optionally substituted heteroaryl, optionally substituted C 5-8  cycloalkyl, optionally substituted C 1-10  alkyl, optionally substituted C 2-10  alkenyl, or an optionally substituted C 2-10  alkynyl;  
                     
 the E′ containing ring is optionally selected from  
                     
 the asterix * denoting point of attachment of the ring;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The method according to  claim 1  wherein the R is (CR 8 R 8 )rC(O) 2 H.  
     
     
         3 . The method according to  claim 1  wherein R 1  is halogen, cyano, nitro, CF 3 , C(O)NR 4 R 5 , alkenyl C(O)NR 4 R 5 , C(O) R 4 R 10 , alkenyl C(O)OR 12 , heteroaryl, heteroarylalkyl , heteroaryl alkenyl, or S(O)NR 4 R 5 .  
     
     
         4 . The method according to  claim 1  wherein R 20  is W 1 .  
     
     
         5 . The method according to  claim 1  wherein R 20  is heteroaryl.  
     
     
         6 . The method according to  claim 4  wherein Y is halogen, C 1-4  alkoxy, optionally substituted aryl. optionally substituted arylalkoxy, methylene dioxy, NR 4 R 5 , thioC 1-4 alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C 1-4 alkyl, hydroxy alkyl.  
     
     
         7 . The method according to  claim 1  wherein R 1  is mono substituted in the 2- or 4-position, or di-substituted in the 2,4-position by an electron withdrawing moiety.